Immunosuppressive agents are used in the treatment of autoimmune disease and in treating or preventing transplantation rejection, including graft-versus-host disease (GVHD). Common immunosuppressive agents include azathioprine, corticosteroids, cyclophosphamide, methotrexate, 6-mercaptopurine, vincristine, and cyclosporin A. In general, none of these drugs are completely effective, and most are limited by severe toxicity. For example, cyclosporin A, a widely used agent, is significantly toxic to the kidney. In addition, doses needed for effective treatment may increase the patient's susceptibility to infection by a variety of opportunistic invaders.
A number of compounds derived from the Chinese medicinal plant Tripterygium wilfordii (TW) have been identified as having immunosuppressive activity, e.g. in the treatment of autoimmune disease, and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD), a condition in which transplanted marrow cells attack the recipient's cells. See, for example, U.S. Pat. Nos. 4,005,108, 5,294,443, 5,843,452, and 5,648,376, cited above.
Triptolide and certain of its derivatives have also been reported to show anticancer activity. See, for example, Kupchan et al., 1972, 1977, as well as co-owned U.S. Pat. No. 6,620,843, which is hereby incorporated by reference.
Triptolide derivatives often provide other benefits relative to native triptolide in areas such as formulation, pharmacokinetics and biodistribution, by virtue of differences in solubility and/or their activity as prodrugs. Such derivatives are described, for example, in Jung et al., U.S. Pat. Nos. 5,972,998 and 6,004,999, and Qian et al., U.S. Pat. No. 5,430,054, as well as co-owned U.S. Pat. No. 6,150,539 (Triptolide prodrugs having high aqueous solubility), U.S. Pat. No. 5,962,516 (Immunosuppressive compounds and methods), U.S. Pat. No. 5,663,335 (Immunosuppressive compounds and methods), and U.S. Pat. No. 6,569,893 (Amino acid derivatives of triptolide compounds as immune modulators and anticancer agents).
In general, these disclosures are directed to derivatives and/or prodrugs produced by synthetic modification of triptolides at the epoxy rings, hydroxyl groups, or the lactone ring. None of these earlier disclosures describe modifications at the 5 or 6 position of triptolide, as disclosed herein.